No convincing animal-model includes evidence of both negative and positive symptoms of schizophrenia, selective pharmacological reversal of these deficits, or provides evidence of its pathophysiological circuits. We have exciting new data in an Old World primate which suggests the possibility of such a model as well as strategies for more effective and selective treatments. PCP is known to induce an enduring schizophrenic-like syndrome with repeated use in humans. Our pilot data in rats and monkeys indicate that subchronic PCP exposure induces a DA deficiency in the PFC and that this deficiency is manifest in cognitive impairment and behavioral abnormalities in the monkey. Further, this cognitive impairment is ameliorated by administration of the atypical antipsychotic drug clozapine, an agent with high efficacy in treating negative symptoms in schizophrenics. Using in vivo and ex-vivo techniques in rats and monkeys, this project will examine the mechanisms responsible for the neurobiological changes induced by repeated PCP administration on the anatomical integrity, neurotransmitter regulation and behavioral functions associated with the PFC. The research plan will investigate the following, hypotheses: (1) Subchronic treatment with PCP induces enduring changes in PFC DA function that persist for more than a month and demonstrates neurochemical and anatomical specificity. (2) The responsivity of the mesoPFC DA system to stress and psychomotor stimulants is blunted suggesting a global functional inhibition of these neurons. (3) Dysregulation of specific auto- or afferent-regulatory control of midbrain DA neurons is responsible for or associated with the observed inhibition of meso-cortical DA function induced by PCP. (4) The behavioral/cognitive deficits induced by repeated PCP exposure are directly related to PFC dysfunction. (5) Atypical will be more effective than typical antipsychotic drugs in reversing,the cognitive deficits, and this difference is dependent on a DA D4 receptor mechanism. The generation of critical neurochemical and behavioral data in the monkey will provide important new insight concerning the neural systems relevant to schizophrenia and aid in the development of novel strategies for ameliorating the neurochemical and behavioral effects in this new, potential animal model of the disorder.